Diabetes mellitus is a highly heterogeneous disease, with several genes and environmental factors playing a pathogenic role. Marked discrepancies in the prevalence of diabetic retinopathy between various ethnic groups and absence of appreciable retinopathy in approximately 20 to 30 percent of juvenile insulin dependent diabetics (JIDD) after many years of disease suggest genetic heterogeneity of retinopathy. We have hypothesized that there are one or more genes determining susceptibility to proliferative diabetic retinopathy (PDR) in linkage with the HLA complex and that these genes play an important pathogenic role. The ability to determine the risk of developing PDR prior to the onset of complications would greatly aid the ophthalmic management of all diabetics. Furthermore, as the cooperative Diabetic Retinopathy Study has shown the effectiveness of photocoagulation in PDR, the ability to determine high risk diabetics would permit the selection of those patients most likely to benefit from "early" photocoagulation. To test this hypothesis we plan to study HLA antigens in highly selected groups of JIDD and adult onset insulin dependent diabetics to determine associations with PDR. In addition, prospective studies of patients enrolled in DRS Phase I and DRS Phase II will be done to determine associations correlated with final visual outcome. Finally, diabetic families, chosen for presence or absence of PDR, will be studied to determine linkage.